Clinical Trials Register

Summary
EudraCT Number:	2020-001101-22
Sponsor's Protocol Code Number:	PURE
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-06-24
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2020-001101-22

A.3

Full title of the trial

Study to evaluate the efficacy and side effects of Envarsus in patients who had a kidney transplantation

Onderzoek bij patiënten met een niertransplantatie naar werking en bijwerkingen van Envarsus

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to evaluate the efficacy and side effects of Envarsus in patients who had a kidney transplantation

Onderzoek bij patiënten met een niertransplantatie naar werking en bijwerkingen van Envarsus

A.3.2

Name or abbreviated title of the trial where available

PURE study

PURE studie

A.4.1

Sponsor's protocol code number

PURE

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Amsterdam UMC
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Chiesi Pharmaceuticals B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Amsterdam UMC
B.5.2	Functional name of contact point	Dr. N. Manson
B.5.3	Address:
B.5.3.1	Street Address	Meibergdreef 9
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1105 AZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+310205665990
B.5.6	E-mail	n.a.manson@amsterdamumc.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Tacrolimus LCPT
D.2.1.1.2	Name of the Marketing Authorisation holder	Chiesi Farmaceutici S.p.A
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Envarsus
D.3.2	Product code	L04AD02
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Envarsus
D.3.9.1	CAS number	109581-93-3
D.3.9.2	Current sponsor code	L04AD02
D.3.9.3	Other descriptive name	TACROLIMUS MONOHYDRATE
D.3.9.4	EV Substance Code	SUB23141
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.75 to 4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Tacrolimus-Extended-Release
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Advagraf
D.3.2	Product code	L04AD02
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Advagraf
D.3.9.1	CAS number	104987-11-3
D.3.9.2	Current sponsor code	L04AD02
D.3.9.3	Other descriptive name	TACROLIMUS MONOHYDRATE
D.3.9.4	EV Substance Code	SUB23141
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.5 to 5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Kidney transplant immunosupression for patients with CYP3A5*1 gene variance

Niertransplantatie immunosupressie voor patienten met CYP3A5*1 gen variant

E.1.1.1

Medical condition in easily understood language

Use of immunosupressive agents after kidney transplant while having a variance in the CYP3A5 gene.

Gebruik van afstootwerende middelen na niertransplantatie bij mensen die een variantie hebben in het CYP3A5 gen.

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Investigative Techniques [E05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10023439
E.1.2	Term	Kidney transplant rejection
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary objective:
The objective is to evaluate if the LCPT dose can be reduced in comparison with tacrolimus-ER and still achieve similar tacrolimus levels in the therapeutic range.

Primair doel:
Het doel is om te evalueren of de LCPT-dosis kan worden verlaagd in vergelijking met tacrolimus-ER dosis en toch vergelijkbare tacrolimus spiegels in het therapeutische gebied te bereiken.

E.2.2

Secondary objectives of the trial

Secondary objectives:
- To evaluate if the switch design of the study leads to a lower pill burden;
- To evaluate if the tacrolimus switch leads to less side effects.
- To evaluate if the tacrolimus switch leads to less variability in trough levels.

Secundaire doelen:
- Evalueren of het switch-design van de studie leidt tot een vermindering van de hoeveelheid pillen die ingenomen moeten worden;
- Evalueren of de wisseling van tacrolimus leidt tot minder bijwerkingen;
- Evalueren of de wisseling van tacrolimus leidt tot minder variatie in de dalspiegels.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

a. Patients aged 18 to 70 years, inclusive, with a stable renal function.
b. Patients who are at least 6 months until two years after first transplantation, who are not immunized with therapeutic tacrolimus concentrations between 5-8 ng/L and on a stable tacrolimus dose with Tacrolimus-Extended-Release with a C/D ratio < 1.05 ng/mL×1/mg.
c. Patients must provide written informed consent.
d. Patients of childbearing potential must agree to use highly effective methods of contraception during the study.

a. Patiënten in de leeftijd van 18 tot en met 80 jaar, met een stabiele nierfunctie.
b. Patiënten bij wie de eerste transplantatie ten minste 6 maanden tot twee jaar geleden is uitgevoerd, die niet zijn geïmmuniseerd met therapeutische tacrolimusconcentraties tussen 5-8 ng/l en een stabiele tacrolimus dosis gebruiken met Tacrolimus Extended Release met een C/D-ratio <1,05 ng/ml × 1/mg.
c. Patiënten moeten een getekende toestemmingsverklaring geven.
d. Patiënten in de vruchtbare leeftijd moeten toestemmen om zeer effectieve anticonceptie te gebruiken tijdens de studie.

E.4

Principal exclusion criteria

a. Patient received or is receiving treatment for acute rejection prior to initiation of study.
b. Donor Specific antibody positivity and patients who are immunized.
c. Chronic diarrhoea.
d. Use of protease inhibitors or miconazoles or sedatives.
e Thyroid dysfunction.
f. Psychiatric or neurological history or use of psychotropic drugs.
g.Use of Beta2-agonists or anti-epileptic drugs.
h. Excessive use of caffeine (more than use of 5 IE daily).
i. Excessive use of alcohol (more than 2 IE daily).
j. Patients who are pregnant.

a. Patiënt kreeg of krijgt een behandeling voor acute afstoting vóór aanvang van de studie.
b. Donor specifieke antilichaam positiviteit en patiënten die geïmmuniseerd zijn.
c. Chronische diarree.
d. Gebruik van protease remmers of miconazolen of kalmerende middelen.
e. Disfunctie van de schildklier.
f. Geschiedenis van psychiatrische of neurologische aandoeningen of gebruik van psychotrope medicijnen.
g. Gebruik van Beta2-agonisten of anti-epileptische medicijnen.
h. Overmatig gebruik van cafeïne (meer dan 5 eenheden per dag).
i. Overmatig gebruik van alcohol (meer dan 2 eenheden per dag).
j. Zwangerschap.

E.5 End points

E.5.1

Primary end point(s)

The dose in mg of Tacrolimus-LCPT (envarsus) needed to reach adequate levels of tacrolimus trough levels in comparison with Tacrolimus-Extended-Release (advagraf).

De dosis in mg van Tacrolimus-LCPT (envarsus) die nodig is om een toereikend niveau van de tacrolimus dalspiegels te bereiken in vergelijking met Tacrolimus-Extended-Release (advagraf).

E.5.1.1

Timepoint(s) of evaluation of this end point

After last patient, last visit

Nadat de laatste patient de laatste visite heeft afgerond

E.5.2

Secondary end point(s)

- variability of trough levels;
- Cmax and Tmax;
- Subgroup analyse of patients in need of 15mg> of Tacrolimus-Extended-Release;
- C/D ratio
- 24hour AUC levels;
- side effects;
- differences in different ethnic groups;
- CYP3A5 genotypes.

- Variabiliteit in dalspiegels;
- Cmax en Tmax;
- Subgroep analyse van patienten die 15 mg of meer Tacrolimus-Extended-Release nodig hebben;
- C/D ratio;
- 24-uurs AUC niveau;
- Bijwerkingen;
- Verschillen in de verschillende etnische groepen;
- CYP3A5 genotypen.

E.5.2.1

Timepoint(s) of evaluation of this end point

After last patient, last visit.

Nadat de laatste patient de laatste visite heeft afgerond.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Switch design

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After completing the study the subjects are allowed to continue their previously prescribed medication (Advagraf) or switch to the medication under study (Envarsus) for an undetermined period of time.

Nadat een proefpersoon de studie heeft afgerond heeft hij/zij de keuze om door te gaan met de medicatie die ze voor de studie al namen (Advagraf) of over te schakelen op de medicatie die binnen deze studie geevalueerd wordt (Envarsus) voor onbepaalde tijd.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-08-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-06-18

P. End of Trial
P.	End of Trial Status	Ongoing

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